Overall With over 250,000 children newly-infected each year, the worldwide HIV-1 epidemic remains an imperative public health challenge for children. Specifically, mother to child transmission (MTCT) of HIV-1 continues to occur at this alarming rate, despite the global scale-up of antiretroviral (ARV)-based prophylaxis during pregnancy and breastfeeding. The inability of ARV-based interventions, alone, to eliminate pediatric HIV-1 infections is due to several challenges, including ARV access/adherence, acute infection of mothers, and the development of drug resistant virus strains. Thus, elimination of pediatric HIV-1 depends on the development of alternate strategies to interrupt MTCT. Strategies involving combined maternal and infant immune-based interventions have been effective against other neonatal pathogens, including hepatitis B and tetanus. In the case of HIV/SIV, previous maternal-infant nonhuman primate vaccine studies from our team members have achieved both partial protection of infants against oral SIV infection and robust, functional neutralizing maternal antibody responses in breast milk. Extending this work, this Program Project grant will test the hypothesis that infant HIV-1 acquisition via breastfeeding can be reduced by an approach combining maternal immunization, to passively immunize the infant with HIV-1 Env-specific antibody (Project 1) and active immunization of the infant (Project 2). Specifically, we will evaluate whether vaccination of mothers and infants with a nonreplicating MVA prime and combined systemic and mucosal transmitted/founder Envelope protein immunogens boost vaccine regimen produced and tested for immunogenicity by Core 1 (Immunogenicity and Vector Development Core) can reduce virus acquisition in a neonatal monkey oral low dose Simian-Human Immunodeficiency Virus (SHIV) challenge model developed by Core 3 (NHP Core). This work will determine if combined maternal and infant immunization can reduce oral virus acquisition in the settings of both acute maternal infection and chronic, ARV-treated maternal infection (Project 1 and 2). Moreover, our studies utilize novel strategies to assess the quality and quantity of Envelope-specific B cell responses in Core 2 (B Cell Core) to decipher the potentially-protective maternal and infant immune responses in this model. Together, the proposed studies will provide understanding of the efficacy and protective mechanisms of combined maternal and infant immunization-information that is crucial to the design of effective maternal and infant HIV-1 vaccines and necessary to end the pediatric HIV-1 epidemic and achieve an HIV-1-free generation.